title: In vitro pharmacological profile of the A2A receptor antagonist istradefylline.
abstract: Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson's disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration-response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic-pharmacodynamic considerations of efficacy and safety.
authors.affiliation: Sales and Marketing Division, Marketing Department, Kyowa Hakko Kirin Co., Ltd., 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo, 100-8185, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Saki
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Etsuko
authors.initials: E
authors.lastname: Koshimura
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Sasaki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kanda
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002144:Callithrix; D002462:Cell Membrane / Q000378:metabolism; D004285:Dogs; D004298:Dopamine / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D016716:PC12 Cells; D011687:Purines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011687:Purines; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; C111599:istradefylline; D004298:Dopamine